Calcium may play a pathogenic role in the generation of atherosclerotic lesions. Atherosclerosis is associsatesd with deposition of calcium in arterial walls, and anticalcifying drugs may suppress atherogenesis. The proposed research is designed to determine whether a calcium-antagonist, nifedipine, suppresses atherogenesis. In adition, experiments are aimed at exploring the question whether arteries chronically exposed to a potent calcium-antagonist become tolerant to the drug or exhibit counter-regulatory sensitization to endogenous constrictors. Rabbits maintained on standard diet or 2% cholesterol diet are treated with nifedipine or placebo for eight weeks. Atherosclerotic changes in the aortas isolated from the rabbits are quantitated by planimetry of the lesions, and assays of tissue cholesterol and calcium. Functional changes are evaluated on the basis of organ bath studies defining the reactivity of aortic strips to selected constrictors (calcium, norepinephrine, angiotensin) and to nifedipine. Results should help to characterize relationships between structural and functional alterations in arteries undergoing atherosclerotic changes. To distinguish between calcium antagonistic effects and non-specific vasodilator effects which may influence atherogenesis, aortas of rabbits treated with a nitrate (isosorbide dinitrate) are studied for comparison. Results should provide information regarding the pathophysiology of atherosclerosis and the pharmacology of calcium-antagonists, agents used with increasing frequency in cardiovascular therapeutics.